I have been developing and applying tools for structure-based drug design. I've been working on the de novo drug design program BUILDER. BUILDER is an interactive model building program run from within MidasPlus. Its purpose is to design novel lead drug compounds, given the 3-D structure of the target receptor. This approach to drug design is to first analyze the receptor for "hot spots" or areas of good potential drug interaction, such as hydrophobic pockets or possible H-bonding sites. Then BUILDER selects appropriate small molecules or fragments to be placed at each of these "hot spots" to maximize drug-receptor binding. Finally the small molecules or fragments are linked together in a chemically sensible way to form a whole molecule. All steps in this process are displayed on MidasPlus, so they can be interactively directed and controlled by the user. The program uses the new delegate feature of MidasPlus to allow interactive use. It has been tested and found to be capable of rebuilding methotrexate from the 4dfr receptor. The Computer Graphics Laboratory facility is vital to this project, since the program needs to be run interactively on the MidasPlus graphics program. In applications, I used BUIL DER to help design a combinatorial library of compounds to inhibit Cathepsin D. This library was compared to one designed using the standard diversity approach. When assayed, we found that the BUILDER library contained a greater number of inhibitors (2-8 fold more), and that these inhibitors were more potent than the ones in the diverse library (top compound about 4 times better). Thus, the structure- based approach was shown to be an improvement over diversity. Other applications have involved the DOCK program. We applied the program DOCK to DNA-binding compounds, and also to look for inhibitors for reverse transcriptase. Again, the Computer Graphics Laboratory is vital in these applications as all results need to be examined and evaluated with computer graphics.